Polymorph forms of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof

Abstract

The present invention relates to polymorphic forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-toluenesulfonate with the characteristic X-ray powder diffraction data as stated in the description, preparation methods thereof, pharmaceutical compositions comprising the same and the use thereof.

The invention claimed is: 
     
       1. A crystalline Form B of a p-Toluenesulfonate salt of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, characterized in that the X-ray powder diffraction pattern has peaks at the diffraction angle 2θ(°) of 4.72±0.10, 17.04±0.10, 19.32±0.10, and 24.12±0.10. 
     
     
       2. The crystalline Form B of a p-Toluenesulfonate salt of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide according to  claim 1 , characterized in that the X-ray powder diffraction pattern also has peaks at the diffraction angle (2θ(°) of 7.92±0.10, 9.54±0.10, 11,90±0.10, 12.94±0.10, 14.34±0.10, 15,32±0.10, 17.88±0.10, 20.00±0.10, 21.80±0.10, 22.42±0.10, 25.08±0.10, 25.80±0.10, 27.28±0.10, 28.00±0.10, and 28.44±0.10. 
     
     
       3. The crystalline Form B of a p-Toluenesulfonate salt of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide according to  claim 1 , characterized in that Form B has the X-ray powder diffraction pattern as substantially shown in  FIG. 2 . 
     
     
       4. The crystalline Form B of a p-Toluenesulfonate salt of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide according to  claim 1 , characterized in that Form B also has the IR spectrum as substantially shown in  FIG. 6 . 
     
     
       5. A pharmaceutical composition comprising a crystalline Form B of an N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-Toluenesulfonate salt and a pharmaceutically acceptable carrier. 
     
     
       6. A process for preparing a crystalline Form B of a p-Toluenesulfonate salt of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, comprising the steps of:
 (a) dissolving a crystalline Form A of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-Toluenesulfonate in the mixture of a protic solvent and an aprotic solvent by heating to form a solution; 
 (b) keeping the solution for 1 to 2 h at the temperature of 40 to 80° C.; 
 (c) cooling the solution and resulting in a crystalline precipitate, letting the resulting mixture stand, filtering out and washing the crystal to obtain the target crystal. 
 
     
     
       7. The process according to  claim 6 , wherein the protic solvent is water or the mixture of water and an alcohol. 
     
     
       8. The process according to  claim 6 , wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, ether, dichloromethane, acetone, acetonitrile, DMF and the mixtures thereof. 
     
     
       9. The process according to  claim 6 , wherein the solution of the crystalline Form A of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-Toluenesulfonate in the step (a) has a concentration of 2˜10 g/100 mL. 
     
     
       10. The process according to  claim 6 , characterized in that the volume ratio of the protic solvent to the aprotic solvent in the mixture of a protic solvent and an aprotic solvent is 1:2˜4. 
     
     
       11. The process according to  claim 6 , characterized in that the protic solvent is water; the aprotic solvent is tetrahydrofuran; the volume ratio of the protic solvent to the aprotic solvent is 1:2˜4] and the solution of the crystalline Form A of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-Toluenesulfonate in the step (a) has a concentration of 2˜10 g/100 mL.